In recent years, evidence has accumulated that ethanol has significant effects on phospholipid-dependent signal transduction systems in a variety of cells and tissues, including liver. The mechanisms of these actions of ethanol may relate to its ability to interact with the phospholipid bilayer and to disturb protein-protein interactions or protein-lipid interactions. As a consequence, ethanol can trigger the generation of a variety of intracellular signals, dependent on phospholipase C and other phospholipases and set into motion a train of events associated with feedback regulation of these signalling systems by protein kinase C, resulting in a desensitization of some hormonal responses in the cell. There is evidence that liver cells from chronically alcoholic rats are tolerant to this heterologous desensitization, associated with changes in the feedback control by protein kinase C. Other hormone-sensitive phospholipases may also be altered in response to chronic ethanol feeding. This study aims a) to elucidate the changes in the phospholipid dependent signalling processes and to investigate the role of protein kinase C isozymes in these changes; b) to analyze the effects of ethanol in vitro on phospholipase- linked signal transduction systems. In addition, the effects of long- term exposure to the anesthetic nitrous oxide on the signal transduction systems in the liver will be compared with those observed after long-term alcohol consumption. Finally, the effects of prolonged treatment with ethanol in vitro on the phospholipid-linked signal transduction processes in a liver-derived cell line, WB cells, will be studied. The results are expected to increase our understanding of defective responses of the liver to hormones and growth factors and to help develop a model by which the mechanism of these adaptive changes can be studied in vitro.